Chronic obstructive pulmonary disease is a heterogeneous disease that is physiologically defined by irreversible loss of lung function. The natural history of COPD is characterized by episodic accentuation of symptoms, exacerbations, which occur in some but not all COPD subjects. COPD exacerbations are a significant public health concern with significant medical, social, and fiscal consequences. As the genetic determinants of exacerbation frequency are unknown, the scientific goal of this project is to study the association of polymorphic variation in innate immunity genes with exacerbations of COPD. We hypothesize that genes involved in innate immunity, the first line of host defense against infection through microbial recognition, influence the susceptibility to develop COPD exacerbations. To test this hypothesis, we will perform genetic association analyses in two ethnically different, community-based populations. We have genotyped a panel of 352 single nucleotide polymorphisms (SNPs) in 51 innate immunity genes and performed association analysis for COPD exacerbations in a subset of participants in the National Emphysema Treatment Trial (NETT). We have selected the most promising 66 SNPs for further study. We will genotype these 66 SNPs in 29 candidate innate immunity genes among subjects with the frequent versus infrequent COPD exacerbation phenotypes in the Fallen HMO/Harvard Vanguard Medical Associates COPD Exacerbation Study;individuals of primarily European descent. Additionally, we will develop a cohort of African American COPD subjects in Atlanta, GA and identify epidemiological predictors of COPD exacerbation frequency. Subsequently, we will test for genetic association of innate immunity genes with COPD exacerbations in this African American cohort, replicating the associations identified in the two Caucasian cohorts. As African Americans are traditionally underrepresented in medical research, the Atlanta cohort will provide a repository of genotypic and phenotypic information that will facilitate future hypothesis testing. By identifying genetic determinants of COPD exacerbations in multiple cohorts, this proposal could greatly contribute to our understanding of the pathogenesis of COPD exacerbations, the similarities and dissimilarities across different groups, and provide insight into the escalating rates for emergency room visits, hospitalizations, and death in African Americans with COPD. (End of Abstract)